Follicular epithelial cell-derived thyroid cancer is the most common endocrine malignancy with a high incidence worldwide (1, 2). This cancer is histologically classified into papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and anaplastic thyroid cancer (ATC) (3). Thyroid cancers frequently harbor activating mutations in the MAP kinase (MAPK) and phosphatidylinositol 3-kinases (PI3K)/Akt signaling pathways (4), as represented by RAS, BRAE, and RET/PTC mutations in the former and PIK3C4 and PTEN mutations in the latter. As an important mechanism for the tumorigenesis of thyroid cancer and many other human cancers, aberrant activation of the two signaling pathways by such mutations can cause uncontrolled cell division, proliferation and survival.
Somatic mutations of GNAQ, MMP8, Akt3, EGER and PIK3R1 genes have been recently reported in some human cancers with various prevalences and they can activate the MAPK and PI3K/Akt signaling pathways (5-10). A particularly frequent somatic mutation of the GNAQ gene at codon 209, resulting in mutant GNAQQ209L, has been reported in uveal melanoma and blue nevi (5). The GNAQ gene encodes a G-protein α subunit that mediates signals from G-protein-coupled receptors (GPCRs) to the MAPK pathway. The normal amino acid, glutamine, encoded by codon 209 of the GNAQ gene ties within the RAS-like domain of GNAQ (corresponding to residue 61 of Ras) and is essential for GTP hydrolysis. Recent studies found no mutation in GNAQ in PTC, MTC and FTC, but it has not been analyzed in the more aggressive type of thyroid cancer, ATC (11-13). Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade components of extra cellular matrix and basement membranes. Abnormalities of MMPs have been associated with cancer metastasis. Frequent mutations of the MMP8 gene have been observed in melanoma (6). Most of the mutations in this gene have been observed in exon 2. All the mutants detected in this exon, including S50F, P78S, K87N and G104R, were shown to be tumorigenic and the wild-type has been shown to inhibit cell growth on soft agar and tumor formation in vivo (6). A point mutation in the pleckstrin homology domain (E17K) and a point mutation in the regulatory C-terminal domain (E438D) of AKT3 were recently found in melanomas (7, 8). Expression of the AKT3 E17K in A375 cells has been demonstrated to increase AKT phosphorylation as compared with the wild-type AKT3 (7). A recent study reported an AKT3 mutation in PTC, but FTC and ATC were not examined in this study (14). Varying frequencies of EGER mutation in PTC had been reported in two studies (9, 15). The status of somatic EGER mutation is not known in this cancer in the American patients, while other types of cancers such as FTC and ATC have been reported (4). The class IA PI3K lipid kinase has a catalytic subunit (p110α) and a regulatory subunit (p85α), which is encoded by PIK3CA and PIK3R1 genes, respectively. Somatic mutations of PIK3G1 gene are common in human cancers. Recently, mutations have also been found in the PIK3R1 gene in human cancers (10). These mutations in PIK3R1 are all shown to promote cell survival, anchorage-independent cell growth and tumorigenesis through AKT activation in a p110-dependent manner (10). The mutation status in the GNAQ, MMP8, AKT3, EGFR and PIK3R1 genes had been incompletely examined or not examined in thyroid cancers.
There is a continuing need in the art to develop a fuller understanding of the genetic factors that affect human cancers so that they can be better identified, treated, and managed.